1. Field of the Invention
The present invention concerns indolone derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals.
2. Description of Related Art
Movement and other disorders due to dysfunction of the basal ganglia and related brain structures are of major socio-economic importance. Such disorders can occur as a consequence of inherited or acquired disease, idiopathic neurodegeneration or they may be iatrogenic. The spectrum of disorders is very diverse, ranging from those associated with poverty of movement (akinesia, hypokinesia, bradykinesia, e.g. in parkinsonian symptomatology), hypertonia (e.g. Parkinson's disease, spasticity) to the involuntary movement disorders (hyperkinesias or dyskinesia, e.g. Huntington's disease, dyskinesia induced by L-3,4-dihydroxyphenylalanine (L-DOPA or levodopa), tardive dyskinesia, progressive supernuclear palsy, multiple system atrophy, corticobasal degeneration, Wilson's disease, progressive pallidal atrophy, the dystonias, metabolic neurotransmitter diseases, tics, tremor, Tourette's syndrome, Sydenham's chorea, restless legs syndrome (RLS), chorea and choreathetosis, paroxysmal dyskinesias, myoclonic disorders, Rett syndrome.
Parkinson's disease and related conditions are amongst of the most prevalent diseases associated with poverty of movement. Parkinsonian symptoms are characterized by slowness of movement (bradykinesia), rigidity and/or tremor. Parkinsonian symptoms are seen in a variety of conditions, most commonly in idiopathic parkinsonism (i.e. Parkinson's Disease) but also following treatment of schizophrenia (i.e. neuroleptic-induced parkinsonism), exposure to toxins/drugs and head injury.
It is widely appreciated that the primary pathology underlying Parkinson's disease is degeneration, in the brain, of the dopaminergic projections from the substantia nigra to the striatum. This has led to the widespread use of dopamine-replacing agents (e.g. L-3,4-dihydroxyphenylalanine (L-DOPA) and dopamine agonists) as symptomatic treatments for Parkinson's disease.
L-DOPA therapy currently offers the best symptomatic treatment of Parkinson's disease and a variety of other movement disorders and most patients will require it during the course of their disease. However, patients will develop L-DOPA-associated motor complications. Problems can include motor fluctuations (e.g. delayed “on” response and dose failure, end-of-dose wearing-off, unpredictable “on-off” response, freezing episodes) and the appearance of a range of side-effects which manifest as abnormal involuntary movements, such as dyskinesia (e.g. peak-dose dyskinesia, “off” dystonia, diphasic dyskinesia). Dyskinesias are usually dystonic or choreiform in nature.
The phenomenon of “end-of-dose wearing-off” generally occurs early in the course of the disease. This is the most common and usually the first type of motor fluctuation that develops. As the name implies, the patient develops a loss of response to a dose of medication before taking the next dose. This occurs more often with levodopa than with the dopamine agonists because the agonists have a significantly longer half-life. Over time, fluctuation from mobility to immobility occurs more frequently, becoming more abrupt and disabling. The response to treatment can become unpredictable, many doses of levodopa having a delayed effect or even no effect at all.
Although many attempts have been made to develop agents that will prevent the development and/or the expression of dyskinesias, just a few were made to find a therapeutic tool able to manage motor fluctuations. Until now, only two classes of drug compounds, the catechol-O-methyltransferase (COMT) and monoamine oxydase type B (MAOB) inhibitors, were developed to lengthen the beneficial therapeutic effect of L-DOPA but some of these compounds show adverse effects.
There is therefore, a need for new add-on therapies to L-DOPA which can enhance its efficacy and/or reduce its adverse effects.
European patent application 0 610 553 discloses 6-bromo-2,3-dihydro-3,3-dimethyl-2-oxo-1H-indol-1-acetamide and 6-bromo-2,3-dihydro-3-methyl-2-oxo-1H-indol-1-acetamide as synthesis intermediates.
Russian patent application SU 841264 discloses 2-(2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide and its anticonvulsant activity
It has now surprisingly been found that certain indolone derivatives demonstrate therapeutic properties which render them useful in a variety of pharmaceutical indications, and particularly for the symptomatic and/or prophylactic treatment of movement disorders and/or motor fluctuations, in particular in Parkinson's disease.